GPCRs Flashcards
1
Q
What is the importance of GPCRs?
A
- GPCRs are activated by a wide variety of ligands, including neurotransmitters, hormones, growth factors, odorant molecules and light, and are encoded by the largest gene family in most animals
2
Q
What is the Structure of GPCRs?
A
- 7 transmembrane domains
- Coupled with G-proteins
- specialised proteins that are able to bind GDP and GTP
- All G-proteins that associate with GPCRs are heterotrimeric (3-subunits)
- alpha, beta and gamma
3
Q
What is the GPCR cycle?
A
- The ligand binds to the GPCR
- When the ligand binds, the GPCR undergoes conformational change
- Alpha subunit exchanges GDP for GTP
- Alpha subunit dissociates and activates or inhibits the effector protein
- Effector protein activates or inhibits signalling cascade
- GTP hydrolysed to GDP
4
Q
What are the effectors of GPCRs?
A
- Adenylyl cyclase
- Phospholipase C
- Direct regulation of K+ and Ca2+ channels
5
Q
What is GPCR regulation of adenylyl cyclase activity?
A
- Signal molecule binds to the receptor causing the GPCR to undergo conformational change
- Alpha subunit exchanges GDP for GTP and a dissociates
- a portion binds to effector protein (adenylyl cyclase)
- Adenylyl cyclase converts ATP to cAMP and releases phosphorus in the process
- cAMP is a 2nd messenger
- increases heart rate
- vasoconstriction
- cAMP is a 2nd messenger
- GTP hydrolysed to GDP
6
Q
G protein a subunits could either be?
A
- Gs = stimulatory G protein
- Gi = inhibitory G protein
7
Q
What is GPCR regulation of phospholipase C activity?
A
- Signal molecule binds to the receptor which causes the GPCR to undergo a conformational change
- a exchanges GDP for GTP and a dissociates
- a portion binds to effector protein (phospholipase C) which hydrolyses PIP2
- The hydrolysis of PIP2 yields DAG and IP2 (act as separate messengers)
8
Q
What does DAG do in GPCR regulation of phospholipase C activity?
A
- Recruits protein kinase C
- cannot happen without Ca2+
9
Q
What does IP2 do in GPCR regulation of phospholipase C activity?
A
- Travels in cytosol, binds to the endoplasmic reticulum receptors
- increases release of Ca2+ in cytosol, enabling specific functions of DAG
10
Q
Direct regulation of ion channels: Activation
A
- Signal molecule binds to receptor which activates
- a exchanges GDP for GTP and a dissociates
- b and gamma directly interacts with K+ channel, where it activates K+ channels, so the K+ flows out
11
Q
Direct regulation of ion channels: Inhibition
A
- Agonist binds the receptor which activates it
- a exchanges GDP for GTP and a dissociates
- b and gamma binds directly to Ca2+ channel and closes it
12
Q
Know GPCR Down-Regulation
A
- If GPCR is overactivated (too high or too frequent drug dose), it will cause the deactivation or down regulation of GPCRs
- Phosphorylation and Arrestins
- Internilisation
13
Q
Know GPCR Down-Regulation: Phosphorylation and Arrestins
A
- Overactivated GPCR stimuluate GPCR kinase to phosphorylate the GPCR on multiple sites making it inactivated
- Once phosphorylation is completed, arrestin will bind to the phosphorylated residues and ultimately closes the whole receptor
- The receptor is then desensitised causing it to be inactive, leading to internilisation causing tissue to be degraded or recycled
14
Q
Know GPCR Down-Regulation: Internilisation
A
- Overactivated GPCR stimulates GPCR kinase to phosphorylate the GPCR on multiple sites, making it inactivated
- Arrestin will bind to the phosphorylated residues, ultimately closing the receptor
- Once receptor is internalised, it is not accessible to ligand anymore and then causes the tissue not to respond any further
- if tissue wants to respond again, it needs to make a new GPCR
15
Q
Mechanism of Action of Pertussis Toxin
A
Inactivates inhibitory G proteins, therefore causing activation
